Abstract
Approximately two out of every five people will be diagnosed with cancer at some point during their lifetime. Significant improvements in cancer care have improved 5-year survival for all cancer sites from 49% in 1980 to 67% currently, such that there are over 14 million people living with cancer in the United States today1. Multiple factors contribute to an increasing prevalence of clinically significant cardiotoxicity during or after cancer treatments. Echocardiography is the mainstay of cardiac assessment before, during, and after cancer treatments. This chapter will review increasing applications of standard and advanced echocardiographic techniques in patients along the entire cancer survivorship continuum that now account for a significant proportion of referrals for echocardiography.
Keywords
cardiotoxicity, cardiovascular complications of radiation therapy, cancer therapy, malignancy
Introduction
Approximately two out of every five people will be diagnosed with cancer at some point during their lifetime. Significant improvements in cancer care have improved 5-year survival for all cancer sites from 49% in 1980 to 67% currently, such that there are over 14 million people living with cancer in the United States today. Multiple factors contribute to an increasing prevalence of clinically significant cardiotoxicity during or after cancer treatments ( Box 42.1 ). Echocardiography is the mainstay of cardiac assessment before, during, and after cancer treatments. This chapter reviews increasing applications of standard and advanced echocardiographic techniques in patients along the entire cancer survivorship continuum that now account for a significant proportion of the referrals for echocardiography.
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Increasing survivorship
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Increasing age and cardiovascular comorbidities of cancer patients
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Increasing range of targeted cancer drugs with potential for cardiovascular toxicity
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Increasing use of combinations of cancer agents and adjuvant thoracic irradiation
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Increasing duration of treatment (e.g., maintenance treatment with BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia)
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Increasing treatment of patients with recurrent or second malignancies with prior exposure to cancer treatments
Introduction
Approximately two out of every five people will be diagnosed with cancer at some point during their lifetime. Significant improvements in cancer care have improved 5-year survival for all cancer sites from 49% in 1980 to 67% currently, such that there are over 14 million people living with cancer in the United States today. Multiple factors contribute to an increasing prevalence of clinically significant cardiotoxicity during or after cancer treatments ( Box 42.1 ). Echocardiography is the mainstay of cardiac assessment before, during, and after cancer treatments. This chapter reviews increasing applications of standard and advanced echocardiographic techniques in patients along the entire cancer survivorship continuum that now account for a significant proportion of the referrals for echocardiography.
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Increasing survivorship
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Increasing age and cardiovascular comorbidities of cancer patients
- •
Increasing range of targeted cancer drugs with potential for cardiovascular toxicity
- •
Increasing use of combinations of cancer agents and adjuvant thoracic irradiation
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Increasing duration of treatment (e.g., maintenance treatment with BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia)
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Increasing treatment of patients with recurrent or second malignancies with prior exposure to cancer treatments
Baseline Assessment Prior to Initiation of Cancer Treatments
Echocardiography should ideally be performed for baseline evaluation of cardiac function prior to initiation of potentially cardiotoxic cancer treatments; however, this often does not occur routinely in clinical practice. At the very least, the authors advocate that pretreatment echocardiography should be strongly considered in the context of any baseline characteristics outlined in Box 42.2 . Furthermore, echocardiography should be part of a more comprehensive baseline cardiovascular (CV) assessment that includes history, physical examination, and electrocardiography. This baseline assessment provides an opportunity to modify proposed cancer treatment protocols if necessary, to optimize pretreatment CV comorbidities, and to identify “higher risk” patients who may warrant closer CV surveillance during cancer treatment, in the hope of minimizing risk of cardiotoxicity.
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Preexisting cardiovascular disease (e.g., ischemic heart disease, valvular heart disease, cardiomyopathies)
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Risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus)
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History of left ventricular dysfunction
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Signs or symptoms of heart failure
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Older patients (>65 years of age)
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Planned treatment with anthracyclines
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Planned treatment with trastuzumab
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Planned treatment with any cancer therapy with higher risk of incident cardiac dysfunction
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Planned surgery as part of cancer treatment that is not considered low risk with respect to morbidity
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Patients with recurrent or second cancers and history of prior chemotherapy exposure and/or thoracic irradiation
During Cancer Treatment
Echocardiography is indicated for patients who develop symptoms and/or signs of cardiac disease during cancer treatment. Echocardiographic surveillance in the absence of clinical symptoms and signs is recommended for certain therapies with significant cardiotoxic potential, such as anthracyclines and trastuzumab. In addition, empiric surveillance using echocardiography is often used for “higher risk” patients with predisposing risk factors for cardiotoxicity undergoing cancer treatment. The primary focus of echocardiographic assessment is to detect cancer therapeutics-related cardiac dysfunction (CTRCD). CTRCD can complicate many cancer therapies and is defined as a decrease in left ventricular ejection fraction (LVEF) of greater than 10%, to a value of less than 53%. CTRCD can be either symptomatic or asymptomatic and can be further categorized based on reversibility as either of the following:
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Reversible CTRCD: LVEF recovery to within 5% of baseline
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Partially reversible CTRCD: LVEF recovery by ≥10% but remains greater than 5% below baseline
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Irreversible CTRCD: LVEF recovery less than 10% and remains greater than 5% below baseline.
The diagnosis of CTRCD should be confirmed by reassessment of LVEF 2–3 weeks after initial detection.
Serial Assessment of Left Ventricular Ejection Fraction
The modified biplane Simpson technique is the method of choice for two-dimensional (2D) echocardiographic assessment of LVEF and left ventricular (LV) volumes. However, this technique is limited by test-retest, and inter- and intraobserver variability, such that changes over time may indicate random measurement or reporting variability rather than true clinically meaningful findings. Indeed, it has been reported that 11% is the smallest change in LVEF that can be recognized with 95% confidence by 2D echocardiographic techniques, which is higher than the difference to be detected based on the definition of CTRCD. Sequential quantification of LVEF and LV volumes in patients undergoing cancer treatments is the exact scenario that calls for better reproducibility due to implications for clinical chemotherapeutic decisions. There are ways to improve reproducibility: contrast echocardiography and 3D echocardiography can reduce temporal and acquisition-related variability in serial LVEF quantification. For a given patient, serial LVEF measurements should be performed using the same technique throughout follow-up, and ideally with the same observer and equipment, to ensure meaningful comparisons.
Contrast Echocardiography
LV opacification with an intravenous contrast agent should be employed when ≥2 contiguous LV segments are not seen on non-contrast 2D echocardiographic apical images. Cancer patients are particularly predisposed to suboptimal echocardiographic windows that warrant consideration for contrast usage as a result of prior surgery (e.g., left mastectomy and breast reconstruction, left thoracotomies). Two-dimensional echocardiographic evaluation of LV volumes and LVEF is more accurate and reproducible when a contrast agent is used. Its use should be consistent at each study time point throughout the surveillance period.
Three-Dimensional Echocardiography
Where available, 3D-echocardiography is the preferred technique for longitudinal assessment of LV function in patients undergoing treatment for cancer. Noncontrast 3D-echocardiography demonstrated significantly lower temporal variability, test-retest variability, and observer variability in a study comparing 2D and 3D techniques with and without contrast administration for serial evaluation of LVEF and LV volumes in patients undergoing chemotherapy over 1 year of follow-up. This is in keeping with a meta-analysis of studies performed in noncancer populations comparing echocardiography and cardiac magnetic resonance imaging (CMR), which demonstrated that 3D-echocardiography is more accurate for LV volumes and LVEF than traditional 2D methods. However, widespread clinical application of 3D-echocardiography in oncology patients is limited by availability, operator experience, cost, and dependence on good 2D echocardiographic-image quality. As the technology becomes more widely available, a 3D-volumetric approach for quantification of LV function will be increasingly used in longitudinal assessment of patients with cancer. At this time, contrast agents are not recommended in conjunction with 3D-echocardiography in the serial assessment of patients with cancer.
Other Imaging Modalities
Echocardiography has emerged as the modality of choice for serial assessment of oncology patients in clinical practice due to widespread availability, relatively competitive cost, absence of radiation exposure, and opportunity to assess cardiac structures other than the LV. If echocardiographic assessment is inadequate for reasons such as poor windows, nuclear multiple gated acquisition (MUGA) scans or CMR may be considered. MUGA scans are well suited for serial assessment of LVEF due to high reproducibility and low variability and were extensively used for this indication in the 1980s and 1990s. However, limitations of radiation exposure and failure to provide any meaningful data beyond LVEF underlie the recent transition to echocardiography in most patients. CMR offers very accurate and reproducible quantification of biventricular function and is particularly suited to evaluate cardiac tumors and pericardial disease. Gadolinium-based imaging techniques are helpful in detection and quantification of myocardial fibrosis that can be a feature of CTRCD. Cost and availability issues, in addition to contraindications to CMR (e.g., pacemakers/defibrillators), limit widespread application of this modality in serial assessment. Nevertheless, it remains a very useful adjunct to echocardiography in select oncology patients. It is important that there is consistent application of the same modality for surveillance for cardiotoxicity in the same patient to facilitate meaningful inter-study comparisons.
Left Ventricular Ejection Fraction Surveillance Schedules
Although the risk associated with specific cancer treatments varies, CTRCD is linked to a large number of traditional cytostatics (e.g., anthracyclines) and newer targeted anticancer drugs that include monoclonal antibodies (e.g., trastuzumab), protein kinase inhibitors (e.g., tyrosine kinase inhibitors), and proteasome inhibitors (e.g., carfilzomib). The 2013 American College of Cardiology Foundation/American Heart Association Guideline for the Management of Heart Failure recognizes this risk of heart failure (HF) by categorizing patients without structural heart disease or symptoms of HF who receive cancer therapies with cardiotoxic potential as having stage A HF and recommend careful optimization of other modifiable risk factors that may lead to or contribute to HF. Although guidelines for cardiovascular surveillance of patients treated with trastuzumab and anthracyclines are available, similar guidelines for surveillance of patients receiving newer cancer therapies are lacking.
Anthracyclines
Anthracyclines are highly effective chemotherapies used in the treatment of many solid and hematological malignancies. Cardinale et al. reported an overall incidence of 9% of cardiotoxicity (defined as a decrease in LVEF by >10% from baseline and absolute LVEF <50%) in a prospective study that performed periodic echocardiography in 2625 patients receiving anthracyclines. A dose-response relationship between cumulative anthracycline exposure and risk of cardiomyopathy is well recognized. Baseline assessment of LVEF should be performed in all patients prior to anthracycline exposure and repeated at any time if signs or symptoms of heart failure develop during or after treatment. For asymptomatic patients, the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines propose repeating LVEF assessment at 6 months after conclusion of anthracycline treatment, annually for 2–3 years thereafter, and then at 3- to 5-year intervals for life. Patients considered at higher risk, such as those exposed to a high cumulative dose of anthracycline (e.g., >300 mg/m 2 of doxorubicin or equivalent) may require more frequent monitoring. Indeed, an expert consensus statement from the American Society of Echocardiography and the European Association of Cardiovascular Imaging advocates for an evaluation of LVEF before each additional cycle of anthracycline once the dose exceeds 240 mg/m 2 . The Children’s Oncology Group Long-Term Follow-up Guidelines recommend lifelong serial echocardiographic screening for survivors of childhood cancers every 1–5 years based on age at treatment, cumulative anthracycline exposure, and whether the heart was irradiated. Given that over 90% of cases of cardiotoxicity occur within the first year of anthracycline treatment, focusing LVEF screening to this higher-risk period could significantly increase yield, as well as physician and patient adherence.
The clinical benefits, yield, and cost effectiveness of LVEF surveillance schedules for detection of asymptomatic LV dysfunction in patients exposed to cardiotoxic cancer therapies are uncertain. Rationalizing lifelong surveillance schedules used in childhood cancer survivors exposed to anthracyclines may be necessary to improve cost effectiveness.
Trastuzumab
Trastuzumab (Herceptin) is a humanized monoclonal antibody directed against the Human Epidermal Growth Factor Receptor 2 (HER2) receptor that is overexpressed in approximately 15% of breast cancers. Use of trastuzumab in HER2 positive breast cancer is associated with significant reduction in cancer recurrence and improvement in survival. However, trastuzumab is well recognized to cause cardiotoxicity. The addition of trastuzumab to chemotherapy regimens is associated with HF in 1.7%–4.1% and LV dysfunction in 7.1%–18.6%, although the incidence is likely higher in clinical practice. Risk factors associated with trastuzumab cardiotoxicity include adjuvant chemotherapy (particularly anthracyclines), advancing age, and CV comorbidities.
Serial evaluation of LVEF is recommended for patients receiving trastuzumab every 3 months during therapy or at any time in the event of clinical signs or symptoms of HF. An algorithm for the continuation and discontinuation of trastuzumab based on LVEF assessment is presented in Fig. 42.1 . Although the role of HF treatment in trastuzumab-induced LV dysfunction has not yet been established, patients are treated according to international guidelines for HF management. In clinical practice, an angiotensin-converting enzyme (ACE) inhibitor is often introduced with the aim of preventing further deterioration in LVEF or development of clinical HF when LVEF is between 40% and 50%.
